Embryonic stem cell signature genes are often activated in multiple types of aggressive tumors, suggesting that the activation of embryonic genes might contribute to the poorly differentiated characteristics of tumors. Squamous cell carcinoma (SCC) of the skin is the second most common skin cancer, with 700,000 new cases every year in the U.S. Although its incidence is lower than that of basal cell carcinoma, its metastatic potential is much greater. Despite the high incidence of skin SCC, our knowledge of the key components and mechanisms underlying its development and progression is still quite limited. Moreover, it is not known whether the embryonic gene program is reactivated in skin SCC as it is in other aggressive types of tumors. It is therefore essential to identify the instrumental components in skin SCC in order to uncover novel targets for improved diagnostic and/or therapeutic intervention. Sox11 is overexpressed in a variety of tumors, but its exact role in cancer is still unclear. Sox11 is a member of the SRY-related high-mobility-group box (Sox) family of transcription factors, which control cell fate and differentiation in a variety of tissue. In skin, Sox11 is expressed in embryonic epidermis; it is absent in adult tissue but is reactivated in skin SCC. Our preliminary studies show that Sox11 overexpression in skin induces hyperproliferation, suppresses differentiation and increases the incidence of tumors. We find that Sox11 overexpression induces the expression of Tcf3, a transcription factor that plays an important role in the regulation of epidermal stem cell fate. We also find that Sox11 overexpressing skins phenocopy Tcf3 overexpressing skins and that overexpression of Tcf3 promotes tumor growth and progression in a mouse model of skin SCC. Based on these data, we hypothesize that overexpression of Sox11 contributes to tumorigenesis through its upregulation of Tcf3. To test our hypothesis and elucidate the role of Sox11 in skin SCC, we propose the following aims: Aim 1: To determine the role of Sox11 in mouse model of skin SCC. To determine how the dysregulation of Sox11 expression contributes to tumor formation, we will employ the DMBA/TPA chemical carcinogenesis protocol on tet-inducible Sox11 transgenic mice and Sox11 conditional knockout mice. Aim 2: To determine the mechanism underlying Sox11's tumorigenic role. To test our hypothesis that Sox11 promotes tumorigenesis through Tcf3 up-regulation, we will evaluate the tumorigenicity of Sox11 overexpression in a Tcf3-deficient background. In parallel, we will identify the cellular processes regulated by Sox11 and determine the extent to which Sox11 affects these processes through its regulation of Tcf3.